Mood Disorders and Addictions: A shared biology?

Dr. Paul Stokes Clinical Senior Lecturer,

Centre for Affective Disorders,

Department of Psychological Medicine

Disclosures

No relevant disclosures:

• No paid lectures for pharmaceutical companies

• No membership of industry advisory boards

• No shareholdings in pharmaceutical companies

• No current or previous industry grant income

Overview

1. Prevalence of co-morbid addictions in mood disorders

2. Impact on clinical outcomes in bipolar disorder

3. Mechanisms

– Dopamine and reward

– GABA-A dysfunction

4. Treatment

– Mood stabilisers

– Atypical antipsychotics

PREVALENCE

Lifetime prevalence of addiction in mood disorders

0

10

20

30

40

50

60

70

% Lifetime prevalence Odds Ratio

ECA study Regier et al JAMA 1990

8X

Lifetime prevalence of alcohol dependence in mood disorders

0

5

10

15

20

25

30

35

Normal Unipolar MDD Bipolar 1 Bipolar 2 Schizophrenia Anxiety disorders

% Alcohol dependence Odds ratio

ECA study Regier et al JAMA 1990

6X

Risk of alcohol dependence in bipolar disorder higher for women than men

Frye et al. Am J Psychiatry 2003

Lifetime prevalence of any drug dependence in mood disorders

0

5

10

15

20

25

30

Normal Unipolar MDD Bipolar 1 Bipolar 2 Schizophrenia Anxiety disorders

% Drug dependence

Odds ratio

ECA study Regier et al JAMA 1990

11X

Lifetime prevalence of comorbid drug abuse in bipolar disorder

Prevalence estimates vary widely between individual drug classes

Bipolar Disorder

• Cocaine: 6%-39%

• Cannabis: 15%-64%

• Opiates: 3%-25%

• Sedatives: 5%-31%

Cassidy et al. Bipolar Disorders 2001

UK national population

• Cocaine: 9%

• Cannabis: 31%

• Opiates: 1%

• Sedatives: 3%

British Crime Survey, Home Office, UK

Bipolar disorder and nicotine addiction

US National Comorbidity survey found that Bipolar Disorder had the highest rates of cigarette smoking of any mental disorder:

• Bipolar Disorder – 3x higher rates

• MDD – 1.5 x increased rates

• Non affective psychosis – 2 x higher rates

Lasser et al JAMA 2000

Behavioural addiction symptoms more common in Bipolar disorder:

• 33% reach cut off for at least one behavioural addiction

• Significantly higher rating scale scores for:

– Pathological gambling

– Compulsive buying

– Sexual and work addiction

Di Nicola et al Journal of Affective Disorders 2010

Zurich Cohort study (20 year follow-up):

• Manic symptoms associated with: – 4x ↑risk of alcohol dependency

– 5x ↑ risk of cannabis abuse/dependence

– 11x ↑ risk of benzodiazepine abuse/dependence

• BP2 associated with: – 21 x ↑ risk of alcohol dependence

– 14x ↑ risk of benzodiazepine abuse/dependence

– No increased risk of cannabis dependence

Merikangus et al Archives Gen Psychiatry 2008

IMPACT ON CLINICAL OUTCOMES

Alcohol misuse associated with more severe mania

Acute mania complicated by current alcohol misuse associated with:

• Higher numbers of manic symptoms

• Increased risk profile:

– More mood lability

– Higher impulsivity levels

– Increased risk of violence

– Increased rates of other drug abuse

Salloum et al Bipolar Disorders 2002

• Remission after an episode of mania less likely in patients with prior substance use

– Particularly alcohol or cannabis use

• Remission more likely in those treated with Valproate or Carbamezepine than Lithium

Goldberg et al J Clin Psych 1999

Co-morbid drug use increases risk of suicide in Bipolar Disorder

0

5

10

15

20

25

30

35

40

Overall Drug use disorder No drug use

% Suicide attempts

Dalton et al. Bipolar Disorders 2003

Other impacts

Co-morbid substance use disorders in bipolar disorder associated with:

• Poorer adherence to medication (Keck et al. 1998)

• Poorer outcomes (Keck et al. 1998)

• Higher relapse rates (Tohen et al 1990)

Probability of not relapsing over 4 years in 24 first episode BD patients (Tohen et al 1990)

A shared neurobiology?: Hypotheses

1. Dopamine and reward

2. GABA dysfunction

MECHANISMS: DOPAMINE

Young men who reported high rates of hypomanic symptoms (Bipolar Phenotype) show blunted subjective responses to alcohol:

• Significantly lower intoxication effects from alcohol

• Higher expectation of positive effect of alcohol

Similar ‘low level response’ to alcohol found in those at high risk of developing alcohol dependence (Volavka et al 1996; Schuckit and Smith 1996)

Yip et al Neuropsychopharmacology 2012

Casey et al Biological Psych 2013

Blunted dopamine release recently found in patients with schizophrenia and substance dependence after an amphetamine challenge

Thompson et al Molecular Psychiatry 2013

Key Question

Are those at risk of developing bipolar disorder also at high risk for addictions due

to a blunted dopamine response to reward?

MECHANISMS: GABA

High rates of co-morbid GAD in mood disorders

Patients with mood disorders have 14 x greater risk of generalised anxiety disorder:

• MDD: 6x

• Bipolar 1: 9x

• Bipolar 2: 5x

Grant et al Psychological Medicine 2005

GABA-A receptor availability reduced in anxiety disorders

GAD

Panic: Malizia et al Arch Gen Psych 1998

PTSD: Bremner et al Am J Psychiatry 2000

GAD: Tiihonen et al 1997

Key Question

Are patients with mood disorders self medicating with alcohol, cannabis and

nicotine to compensate for a deficit in the GABA system ?

TREATMENT: MOOD STABILISERS

How to treat pharmacologically?

Lithium

• May not be effective in bipolar variants such as dysphoric, mixed, or rapid cycling, which are overrepresented in bipolar alcoholic patients.

• Lithium carbonate was ineffective in decreasing alcohol consumption in a large multicenter trial of depressed alcoholics (Dorus et al JAMA 1989)

• 24 week trial in Bipolar 1 patients & alcohol dependence

• All received ‘treatment as usual’: Li, detox if necessary, psychosocial interventions for SUD

• Valproate group had – Less heavy drinking ; related to valproate plasma levels;

improved GGT in Valproate group

• No difference in improvement of symptoms of mania or depression between groups

Salloum et al. Am J Psych 2005

• Alcohol, cocaine, cannabis dependence or abuse.

• BPD responders more likely to be no longer abusing drugs

• No difference in primary outcome : relapse to new mood episode

Most patients did not ‘stabilize’ (31 vs 118) – difficult trial to do / condition

Kemp et al., J Clin Psychiatry 2009 70(1) 113-121

Open label study of effect of 300mg lamotrigine on mood and cocaine use

Improvements in:

• Depression and mania symptoms (HAMD, YMRS scores)

• Cocaine craving

• Dollars spent per week on cocaine

Sherwood Brown et al J Affect Disorders 2006

TREATMENT: ANTIPSYCHOTICS

• Randomised to lithium or valproate, then randomised to placebo or quetiapine (n=362, 42% completed).

• No significant change in heavy drinking or Clinical Global Impressions at 12 weeks.

Heavy drinking

CGI

Mania

Depression

• Improvements in cocaine craving with both drugs

• Changes in mood not significantly associated with cocaine use

• Risperidone: 3.1 + 1.2mg/d

• Quetiapine: 303.6 + 150.7mg/d

• No placebo group

Challenges in assessing treatment effects

• Small number of studies overall

– e.g. No controlled trials of nicotine cessation for smokers with bipolar disorder available

• Most studies available are case studies or open label trials studying small numbers of patients with relatively short follow-up

• Very few well powered RCT’s investigating treatment effects in co-morbid patients

Summary 1

• Rates of alcohol and drug dependence much higher in bipolar disorder and also elevated in MDD

• BP2 and manic symptoms are risk factors for developing drug and alcohol abuse and dependence

• Co-morbidity impacts on clinical outcomes: increased risk of suicide, slower recovery and higher rates of admissions

Summary 2

• Co-morbidity may be mediated by the dopamine-reward system or by impaired GABA function

• Mood stabilisers and antipsychotics may be effective in treating co-morbid addictions although evidence base is poor

Clinical implications 1

• Look carefully for a history of co-morbid drug and alcohol dependence in patients with mood disorders (particularly BD) and vice versa

• Educating patients that they are at increased risk for substance dependence and the role that drug and alcohol use has in worsening outcomes in bipolar disorder is important

Clinical implications 2

• Treat mood episodes as recommended in guidelines e.g. NICE, BAP however assess contribution of substance misuse to hypomania or mania in BD and consider if medically assisted withdrawal is required

• Review pharmacotherapy for bipolar disorder particularly if only on lithium, and consider adding sodium valproate.

Acknowlegments

• Allan Young (Centre for Affective Disorders, Kings College London)

• Anne Lingford Hughes (Centre for Neuropsychopharmacology, Imperial College London)

• David Nutt (Centre for Neuropsychopharmacology, Imperial College London)

BRITISH ASSOCIATION FOR PSYCHOPHARMACOLOGY

40th Anniversary

Summer Meeting

20 ̶̶̶̶̶̶̶̶̶ 23 July 2014

Cambridge

Online CPD Resource

Schizophrenia Substance misuse including comorbidity Bipolar disorder Perinatal disorders ADHD focussing on adults Depression Anxiety disorders Sleep Old Age Child and Adolescent (coming soon)

www.bap.org.uk

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THANK YOU Dr. Paul Stokes Centre for Affective Disorders, Department of Psychological Medicine Institute of Psychiatry at King's College London Main Building, 4th floor, Room M4.01.01, De Crespigny Park London SE5 8AF Tel: +44-(0)20 7848 5088 e-mail: paul.r.stokes@kcl.ac.uk